Studies on the synthesis and evaluation of key analogs and partial structures of the glycopeptide antibiotics including vancomycin, teicoplanin, and ristocetin are detailed. This includes efforts to re-engineer vancomycin to bind D-Ala-D-Lac to address the emerging bacterial resistance derived from peptidoglycan remodeling of D-Ala-D-Ala, efforts to define and optimize the role of aryl chlorides, and the full exploration of a new class of glycopeptide derivatives discovered in the last grant period that are active against VanB and VanA resistant bacteria. These studies should establish the feasibility of re-engineering vancomycin to bind D-Ala-D-Lac, may provide several unique approaches to countering the emerging vancomycin resistance, and will provide a fundamental understanding of the structure-function relationships of the glycopeptide antibiotics. An exciting complement to these studies is the detailed exploration of ramoplanin which is similarly designed to refine the understanding of its mechanism of action, define the structural details of its binding to lipid II, and to establish key structural features contributing to tranglycosylase inhibition and antimicrobial activity. Extensions of these studies are detailed for the total synthesis of the chloropeptins (anti HIV activity) and structural analogs, chlorofusin (inhibitor of p53-MDM2 binding displaying antitumor activity) and an extensive series of analogs in efforts that will also define its chromophore absolute stereochemistry, HUN-7293 (identification of its biological target for inhibition of VCAM-1 expression and its anti-inflammatory activity), and for the total synthesis of RP-66453 defining its relative and absolute stereochemistry.